Analgesic agent and its use

ABSTRACT

Aqueous pharmaceutical compositions comprising levobupivacaine((S)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide), that are particularly useful in a patient who is disposed to adverse systemic side-effects, are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.08/549,408, filed Oct. 27, 1995, now U.S. Pat. No. 5,849,763; which is acontinuation-in-part of PCT/GB94/02249, filed Oct. 13, 1994.

FIELD OF THE INVENTION

This invention relates to a new therapeutic use for levobupivacaine or(S)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide.

BACKGROUND OF THE INVENTION

Racemic bupivacaine is an effective long-acting local anaesthetic, andmay be given as an epidural. However, racemic bupivacaine iscardiotoxic, having depressant electrophysiological and mechanicaleffects on the heart. It should therefore be used with caution incardiac-compromisedpatients, and the use of high doses and highconcentrations is contraindicated.

In particular, bupivacaine has produced death in a number of patients,including women in childbirth and when used in the Bier's blocktechnique. Although the incidence of death has been relatively small,the concern has been sufficient to stop the use of 0.75% bupivacaine forobstetrics and the prescribing of bupivacaine for use in Bier's blocks.

In addition, due to its mode of action, directly on the nervous system,at higher doses bupivacaine is known to have undesirable central nervoussystem (CNS) side-effects which, prima facie, are connected to itsanaesthetic activity. Indeed, the occurrence of CNS side-effects is oneof the major factors limiting the use of this drug in normal clinicalpractice employing techniques such as local infiltration, nerve block,field block, epidural and spinal blocks.

It is known that levobupivacaine is probably less cardiotoxic thandexbupivacaine and racemic bupivacaine. See, for example, Vanhoutte etal. (1991) Br. J. Pharmacol. 103:1275-1281, and Denson et al. (1992)Regional Anaesthesia 17:311-316. Vanhoutte et al. studied the effects ofbupivacaine enantiomers on the electrophysiological properties of guineapig isolated papillary muscle; this is based on their statement that"the cardiotoxicity of bupivacaine seems to be mainly ofelectrophysiological origin."

BRIEF SUMMARY OF THE INVENTION

Surprisingly, it has now been found that while levobupivacaineretainsthe anaesthetic activity of the racemate, it produces less CNSside-effects, i.e., the CNS side-effects and the anaesthetic activity oflevobupivacaine are not interrelated in the same manner as in racemicbupivacaine. Expressed in another way, the therapeutic ratio oflevobupivacaine with respect to CNS side-effects is unexpectedly higherthan it is for the racemic drug. This, coupled with the known reducedcardiac side-effects of levobupivacaine, means that levobupivacaine isuseful as a local anaesthetic, particularly in clinical procedures wherethe risk of systemic exposure to the drug is increased, and harmfulside-effects are associated therewith. Indeed, it may be useful in anyclinical procedure in which the racemic drug has, or may have, adebilitating effect. In addition, while levobupivacaine can be used atdoses conventionally used for the racemic drug, it can also be used athigher doses and/or over longer periods, formerly contraindicated forthe racemic drug, enabling better anaesthesia, e.g., in terms ofavailability to different patient types, extent of anaesthetic blockachieved, etc., without the adverse effects conventionally associatedwith these dose regimens.

According to a first aspect of the present invention, a method ofproviding anaesthesia, in particular without concomitant adversesystemic side-effects (e.g., CNS), in a patient, comprises administeringto the patient an effective amount of levobupivacaine.

According to a second aspect of the present invention, a method ofproviding anaesthesia in obstetrics comprises administering to a patientlevobupivacaine.

According to a third aspect of the present invention, a pharmaceuticalcomposition comprises a solution, preferably aqueous, having aconcentration of greater than 0.75% w/v of levobupivacaine, measured asthe free base.

According to a fourth aspect of the present invention, a unit dose oflevobupivacaine comprises an ampoule containing the above-describedcomposition.

DETAILED DISCLOSURE OF THE INVENTION

For the purpose of the present invention, CNS side-effects includeeffects such as tinnitus, numb tongue or lips, and dry mouth, and arethe early indicators of direct nervous system effects. For instance, CNSside-effects are typically used as warnings of the onset of convulsions(which in a pregnant woman may also be induced in utero) which must beavoided because of the risk to the patient, e.g., death, brain damage,foetal distress, etc. As a result, clinical administration of a localanaesthetic is stopped upon onset of these early symptoms, whether ornot adequate anaesthesia or analgesia has been achieved. The dose atwhich CNS side-effects appear varies greatly between patients and cannotbe predicted reliably.

In the method of the present invention, levobupivacaine may be providedin solution, for infusion or injection into the epidural or spinalspace, or for administration by any of the conventional means forobtaining a nerve or field block. In addition to the anaesthetic blocksconventionally provided by the racemate, levobupivacaine may also beuseful in providing blocks in areas of the body where the risk ofsystemic exposure to the drug, and therefore CNS side-effects, isparticularly high. Examples include open wounds and vascular areas, forinstance using intercostal blocks for the latter.

Administration of levobupivacaine may be continuous or bolusadministration. This may be done using conventional apparatus, e.g.,including means for the patient to induce infusion as desired. The dailydose administered to the patient may be in the relatively low rangeknown for the administration of racemic bupivacaine but, because of thedecreased CNS side-effects of levobupivacaine, may be higher than theconventional dose for the racemic drug. For instance, the patient mayreceive a daily dose of levobupivacaine of up to about 2500 mg. However,it is preferred to provide a considerable safety margin for the patientand, therefore, for the patient to receive a daily dose of less thanabout 2000 mg. Consequently, the total dose of levobupivacaine may bearound, or in excess of, about 2 mg per kg of patient body weight.

The concentration of levobupivacaine to be given can be thatconventionally used for the racemic drug. However, the concentration istypically higher than this, for instance, at least about 0.75% w/v, andcan be up to about 2% w/v. Preferably, however, the concentration oflevobupivacaine is in the range of about 0.8% to about 1.5% w/v, andmore preferably a concentration of about 1%, 1.25%, or 1.5% w/v is used.The solution is preferably aqueous.

The solution may typically be put up in unit doses of from about 1 toabout 15 ml, and preferably of about 10 ml. However, the unit doses maybe higher, for example, up to about 40 ml or higher. The unit doses mybe in the form of ampoules, which may be made of any suitable material,e.g., glass or an appropriately impervious plastic material. Unitdosages comprising at least about 75 mg, but preferably less than about200 mg, of levobupivacaine can be administered, and more preferably theunit dosage is in the range of about 80 to about 150 mg. Consequently,the patient may receive a daily dose of levobupivacaine of up to about2500 mg, but it is preferred that the daily dose is less than about 2000mg.

The administration of levobupivacaine over a range of concentrations,including those currently used for the racemic drug and the higherconcentrations described above, can be carried out for significantlylonger periods than at present, again as a result of the reduced CNSside-effects experienced with levobupivacaine. For example,levobupivacaine can be administered to a patient safely for at least 24hours, often up to 72 hours, and even for periods of up to a week or afortnight, or longer. It can, of course, be administered for similarperiods already used for the racemic drug, e.g., between about 3 and 6hours.

The method of the present invention is particularly useful in surgicalprocedures carried out on patients who are cardiac- or CNS-compromised,or patients predisposed to cardiac- or CNS-related conditions, i.e.,having a low CNS threshold. Alternatively, the patient may be one inwhich the direct nervous system effects following CNS side-effects areparticularly dangerous, or even lethal, e.g., a pregnant woman, andespecially a woman in, or about to start, labour or to undergo Caesariansection.

The levobupivacaine used in the present invention is preferablysubstantially free of dexbupivacaine, and is more preferably in at least90%, and most preferably at least 99%, enantiomeric excess with respectto dexbupivacaine. Throughout this specification, reference tobupivacaine and its enantiomers includes pharmaceutically-acceptablesalts thereof.

Following are examples which illustrate procedures for practicing theinvention. These examples should not be construed as limiting. Allpercentages are by weight and all solvent mixture proportions are byvolume unless otherwise noted.

Example 1--Physiological Effects of Levobupivacaine Administration

The cardiovascular and central nervous (CNS) effects of levobupivacainewere compared with racemate (Marcaine) in healthy male volunteers. Drugswere administered by intravenous administration in a double-blindcrossover manner. The infusion rate was 10 mg/minute for each drug, andinfusion was continued up to a maximum of 150 mg or stopped followingthe first detection of CNS effects (including tinnitus, numb tongue orlips, and dry mouth). Volunteers were previously conditioned to the CNSeffects of local anaesthetics by administration of a test dose oflignocaine. A range of cardiovascular parameters were measured,including systolic and diastolic blood pressures, ECG, and, using thetransthoracic electrical bioimpedance technique (with a BoMedNCCOM3-R7), aortic blood flow, allowing measurements of cardiac indexand stroke index. Based on results from a previous study in whichracemic bupivacaine was infused, it was anticipated that the majorcardiovascular changes observed following bupivacaine administrationwould be related to myocardial contractility. Therefore, an accelerationindex, representing the initial maximum acceleration of blood flowduring the onset of ejection, was measured to estimate myocardialcontractility in this new study.

Levobupivacaine, like racemate, was well tolerated. The mean total dosesadministered of levobupivacaine and racemate, before the onset of CNSeffects, were 54.0 and 45.6 mg, respectively, and plasma concentrationsat the end of infusion were 2.384 μg/ml and 1.87 μg/ml, respectively(n=12). Despite the mean total dose and plasma concentration beinghigher with levobupivacaine,this produced much smaller mean changes incardiac variables than the racemate. The myocardial contractility indexwas significantly reduced by bupivacaine from a value of 1.36 S⁻² to1.18 S⁻², a decrease of 0.18 S⁻² or 13%. For levobupivacaine,thepre-dose value was 1.34 S⁻², and this only decreased to 1.28 S⁻² at theend of infusion, a decrease of 0.06 S⁻² or 4.5%. The difference betweendrug treatments was highly significant (p<0.02, n=12). The results weresimilar for stroke index, a parameter likely to reflect changes inmyocardial contractility. Bupivacaine reduced this from 55.3 ml/M² to44.4 ml/M², a decrease of 10.9 ml/M² or 20%. For levobupivacaine, thepre-dose value was 52.4 ml/M² and 49.1 ml/M² at the end of infusion, adecrease of 3.3 ml/M² or 6%. Again, the difference between drugtreatments was statistically highly significant (p<0.01, n=12). Smallchanges in other variables occurred including heart rate and mean bloodpressure (increases) and ejection fraction and cardiac index(decreases). As with acceleration index and stroke index, the changestended to be greater with bupivacaine.

As is apparent from the above, a larger quantity of levobupivacaine wasrequired to stimulate CNS effects than racemic bupivacaine: in the 12volunteers, the mean total dose of levobupivacaine administered was 54.0mg compared with 45.6 mg of racemic bupivacaine.

Example 2--Composition of an Aqueous Solution of Levobupivacaine

A sterile isotonic solution of levobupivacaine was made up using thefollowing components:

1.00 g of levobupivacaine hydrochloride (measured as the free base)

0.9 g of sodium chloride

to 100 ml water for injection

The solution was made up under sterile conditions (alternatively, itcould have been sterilized after make-up, e.g., by sterile filtration).

10 ml aliquots of the solution were filled into sterilized glassampoules, which were then sealed ready for use.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims.

What is claimed is:
 1. A pharmaceutical composition comprising asolution of at least 0.75% w/v of levobupivacaine, measured as the freebase; wherein the concentration of levobupivacaine is less than 2% w/v;and wherein said levobupivacaine is present in at least a 90%enantiomeric excess with respect to dexbupivacaine.
 2. The composition,according to claim 1, wherein the concentration of levobupivacaine is inthe range of from 0.75% to 1.5% w/v.
 3. The composition, according toclaim 2, wherein the concentration of levobupivacaine is selected fromthe group consisting of 0.75%, 1%, 1.25%, and 1.5% w/v.
 4. Thecomposition, according to claim 1, which is an aqueous solution.
 5. Thecomposition, according to claim 1, wherein the levobupivacaine issubstantially free of dexbupivacaine.
 6. A unit dose of levobupivacainecomprising an ampoule containing a composition according to claim
 1. 7.The unit dose, according to claim 6, containing 1 to 15 ml of thecomposition.
 8. A pharmaceutical composition comprising a solution of0.75% w/v of levobupivacaine, measured as the free base; and whereinsaid levobupivacaine is present in at least a 90% enantiomeric excesswith respect to dexbupivacaine.